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DeSoto County was created in 1887. It was named for Spanish explorer Hernando de Soto, whose name was also honored in Hernando County. DeSoto County originally included several other present-day counties until 1921, when the Florida legislature created the following new counties: Charlotte, Glades, Hardee, and Highlands.

During World War II, DeSoto County operated the Carlstrom Field Air Base, which provided training for both American and British pilots. Twenty-three British pilots were killed while training at the base and are honored at DeSoto County's Oak Ridge Cemetery, which is located in the town of Arcadia. In 1945, the base turned out its last cadets and was decommissioned. The base was then sold to the State of Florida for one dollar and later converted into a mental health facility known as G. Pierce Wood Memorial Hospital. The hospital has since been converted into a facility for juvenile offenders.

On August 13, 2004, Hurricane Charley passed directly through DeSoto County. Hurricane-force winds persisted for an hour, damaging most of the structures in the county and causing some to be completely destroyed.